Geometric Constraints Regulate Energy Metabolism and Cellular Contractility in Vascular Smooth Muscle Cells by Coordinating Mitochondrial DNA Methylation. Issue 32 (14th September 2022)

• Record Type: Journal Article
• Authors: Liu, Han; Liu, Yuefeng; Wang, He; Zhao, Qiang; Zhang, Tao; Xie, Si‐an; Liu, Yueqi; Tang, Yuanjun; Peng, Qin; Pang, Wei; Yao, Weijuan; Zhou, Jing
• Is Part Of: Advanced science. Volume 9:Issue 32(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-09-14
• Subjects: cPLA2 -- DNMT1 -- geometric constraint -- mitochondrial DNA methylation -- smooth muscle contractility; Science -- Periodicals; 505
• DOI: 10.1002/advs.202203995
• Languages: English
• ISSNs: 2198-3844

Abstract

Abstract: Vascular smooth muscle cells (SMCs) can adapt to changes in cellular geometric cues; however, the underlying mechanisms remain elusive. Using 2D micropatterned substrates to engineer cell geometry, it is found that in comparison with an elongated geometry, a square‐shaped geometry causes the nuclear‐to‐cytoplasmic redistribution of DNA methyltransferase 1 (DNMT1), hypermethylation of mitochondrial DNA (mtDNA), repression of mtDNA gene transcription, and impairment of mitochondrial function. Using irregularly arranged versus circumferentially aligned vascular grafts to control cell geometry in 3D growth, it is demonstrated that cell geometry, mtDNA methylation, and vessel contractility are closely related. DNMT1 redistribution is found to be dependent on the phosphoinositide 3‐kinase and protein kinase B (AKT) signaling pathways. Cell elongation activates cytosolic phospholipase A2, a nuclear mechanosensor that, when inhibited, hinders AKT phosphorylation, DNMT1 nuclear accumulation, and energy production. The findings of this study provide insights into the effects of cell geometry on SMC function and its potential implications in the optimization of vascular grafts. Abstract : Two‐dimensional and three‐dimensional modeling of vascular smooth muscle cell geometry provides a platform for studying how cells respond to the physical stimuli. A critical role of the cPLA2‐AKT mechanotransduction cascade in sensing nuclear shape and modulating DNMT1 nuclear‐mitochondrial distribution is demonstrated. The findings indicate geometry a crucial determinant of cellular contractility and energy metabolism.